Imaging of coronary atherosclerosis and vulnerable plaque Velzen, J.E. van

Imaging of coronary atherosclerosis and vulnerable plaque

Velzen, J.E. van

Citation

Velzen, J. E. van. (2012, February 16). Imaging of coronary atherosclerosis and vulnerable plaque. Retrieved from https://hdl.handle.net/1887/18495

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/18495

Note: To cite this publication please use the final published version (if

applicable).

CHAPTER 4

The Site of Greatest Vulnerability is Most Often Located Proximally to the Site of Most Severe

Narrowing: A Virtual Histology Intravascular Ultrasound Study

Joëlla E. van Velzen, Michiel A. de Graaf, Fleur R. de Graaf, Joanne D.

Schuijf, Jouke Dijkstra, Jeroen J. Bax, Johan H.C. Reiber, Martin J. Schalij, Ernst E. van der Wall, J.Wouter Jukema

Submitted

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ABSTRACT

Background: Previous angiographic studies have shown that almost two-thirds of vulner- able plaques are located in non-obstructive lesions. Possibly, the site of greatest vulner- ability is not always located at the site of most severe stenosis. Therefore, the purpose of this study was to evaluate the difference in location between the site of greatest vulner- ability and the site of most severe narrowing as assessed by virtual histology intravascular ultrasound (VH IVUS).

Methods: Overall, 77 patients (139 vessels) underwent VH IVUS. The site of greatest vul- nerability was defi ned as the cross-section with the largest necrotic core area per vessel, the maximum necrotic core (Max NC) site. The site of most severe narrowing was defi ned as the minimum lumen area (MLA). Per vessel the distance from both the Max NC site and MLA site to the origo of the coronary artery was evaluated. In addition, the presence of a thin cap fi broatheroma (TCFA) was assessed.

Results: The mean difference (mm) between the MLA site and Max NC site was 10.8±20.6mm (P<0.001). Interestingly, the Max NC site was located at the MLA site in 7 vessels (5%) and proximally to the MLA site in 92 vessels (66%). Importantly, a higher % of TCFA was demonstrated at the Max NC site as compared to the MLA site (24% versus 9%, P<0.001).

Conclusion: The present fi ndings demonstrate that the site of greatest vulnerability is

rarely at the site of most severe narrowing. Most often, the site of greatest vulnerability is

located proximally to the site of most severe narrowing.

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INTRODUCTION

Previous angiographic studies have shown that almost two-thirds of vulnerable plaques are located in non-obstructive atherosclerotic lesions.

Nevertheless, at present, inter- ventional strategies are mainly targeted towards management of acute coronary syn- dromes at the site of most severe luminal narrowing. Whether this approach adequately covers the more vulnerable regions remains uncertain. Thus far, the spatial relationship between the location of most severe narrowing and vulnerable rupture sites has not been fully elucidated.

Virtual histology intravascular ultrasound (VH IVUS) is a promising tool for the assess- ment of plaque composition.

Using spectral analysis of radiofrequency backscatter signals, this technique has the ability to evaluate 4 plaque components, namely fi brotic, fi bro-fatty, necrotic core and calcifi ed tissue. The accuracy of VH IVUS for the determina- tion of plaque components has been validated against histopathology in human coronary arteries and was 90.4% for fi brous, 92.8% for fi bro-fatty, 89.5% for necrotic core and 90.9% for dense calcium.

Recently, a large prospective multi-centre study by Stone et al.

showed a strong predictive value of the presence of thin cap fi broatheroma (TCFA) on VH IVUS.

In a cohort of 697 patients, the presence of TCFA on VH IVUS was demonstrated to be an independent predictor of major adverse cardiovascular events.

The aim of the present study was to improve understanding of the spatial relationship between the location of the site of greatest vulnerability and the location of most severe narrowing. Therefore, we compared the location of the maximum necrotic core area (site of greatest vulnerability) with the location of the minimum lumen area (site of most severe narrowing) with VH IVUS.

METHODS Patients

The study population consisted of 77 patients with chest pain referred for invasive coro- nary angiography (ICA). Patients were clinically referred for invasive coronary angiogra- phy because of known or suspected coronary artery disease (CAD). Referral for invasive coronary angiography was based on clinical presentation and/or imaging results. VH IVUS was performed to further evaluate the extent and severity of disease. Both patients presenting with stable chest pain and acute coronary syndrome (ACS) were evaluated.

Patients with ACS included unstable angina and non-ST-segment elevation myocardial

infarction defi ned according to the guidelines of the European Society of Cardiology

and the American College of Cardiology (ACC)/American Heart Association.

Patient data

were prospectively collected in the departmental Cardiology Information System (EPD-

Vision®, Leiden University Medical Center, Leiden, the Netherlands) and retrospectively

analyzed. Contra-indications for VH IVUS were severe vessel tortuosity, severe luminal

narrowing or (subtotal) vessel occlusion. In each patient the presence of CAD risk factors

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such as diabetes, hypertension, hypercholesterolemia, positive family history, smoking and obesity, was recorded.

VH IVUS acquisition

VH IVUS was performed according to standard clinical protocol during ICA using a novel dedicated IVUS-console (s5

Imaging system, Volcano Corporation, Rancho Cordova, CA, USA). After local intracoronary admission of 200 μg nitroglycerin, VH IVUS was performed with a 20 MHz, 2.9 F phased-array IVUS catheter (Eagle Eye, Volcano Corporation, Rancho Cordova, CA, USA). The IVUS catheter was positioned distally in the coronary artery and motorized automated IVUS pullback was performed using a speed of 0.5 mm/s until the catheter reached the guiding catheter. Images were obtained at the R-wave peak on the ECG. At an average heart rate of 60/min, the incremental distance between frames was approximately 0.5 mm. Cine runs were performed to record the starting position of the VH IVUS catheter. Images were stored on DVD for further offl ine analysis.

VH IVUS analysis

Images were analyzed offl ine using specially developed dedicated software for images acquired on the s5

IVUS Imaging system (QCU- CMS 4.59, Medis, Leiden, The Nether- lands). Vessels without evidence of major atherosclerotic plaque (plaque burden <40%) or with previous stent placement were excluded from further analysis. All IVUS examinations were evaluated by two experienced observers. First, the IVUS run was visually assessed to confi rm that the pullback had been performed at a constant speed.

Second, contour detection of the external elastic membrane (EEM) and lumen was performed. The area enclosed by the contours of EEM and lumen was defi ned as plaque area. Percentage plaque burden was calculated as plaque cross-sectional area (CSA) plus media CSA divided by EEM CSA multiplied by 100 according to the American College of Cardiology Clinical Expert Consensus Document on Standards for Acquisition, Measure- ment and Reporting of Intravascular Ultrasound Studies (IVUS).

Subsequently, using radiofrequency backscatter analysis, four plaque components were differentiated into color codes as validated previously.

Accordingly, fi brotic tissue was labeled in dark green, fi bro-fatty in light green, dense calcium in white and necrotic core in red.

The site of most severe narrowing was defi ned as the cross-section with the small- est cross-sectional lumen area in the entire vessel, the minimum lumen area site (MLA).

Multiple defi nitions are available to defi ne the site of greatest vulnerability on VH IVUS. As

amount of necrotic core is quantifi able on VH IVUS, the site of greatest vulnerability was

defi ned as the cross-section with the largest necrotic core area per vessel, the maximum

necrotic core (Max NC) site. Subsequently, per vessel, the maximum necrotic core (Max

NC) site and MLA site were identifi ed. First, in each vessel the distance from both the Max

NC site and MLA site to the ostium of the coronary artery was measured with a dedicated

software tool in the longitudinal IVUS view. Distances were calculated based on the pull-

back speed of motorized automated pullback at a rate of 0.5 mm/s. Difference between

both sites was calculated as distance from MLA site to origo minus distance from Max NC

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site to origo. Furthermore, classifi cation of plaque type and composition was performed at both the Max NC site and MLA site. Plaque components were reported as absolute values and percentages of plaque area. In addition, visual plaque type classifi cation was obtained according to the following categorization:

1. Pathological intimal thickening; defi ned as a mixture of fi brotic and fi bro-fatty tissues, a plaque burden ≥40% and <10% necrotic core and dense calcium.

2. Fibroatheroma; defi ned as having a plaque burden ≥40% and a confl uent necrotic core occupying 10% of the plaque area or greater in three successive frames with evidence of an overlying fi brous cap.

3. TCFA; defi ned as a lesion with a plaque burden ≥40%, the presence of confl uent necrotic core of >10%, and no evidence of a large fi brous cap.

4. Fibrocalcifi c plaque; defi ned as a lesion with a plaque burden ≥40%, with dense calcium >10% and a percentage necrotic core of <10% (higher amount accepted if necrotic core was located exclusively behind the accumulation of calcium).

Statistical analysis

Statistical analyses were performed using SPSS (version 17.0, SPSS Inc., Chicago, IL, USA).

First, the spatial relationship (in mm) between Max NC and MLA site was assessed. In a sub-analysis, the impact of clinical presentation (patients with stable CAD versus patients with ACS) and the difference in length between the Max NC and MLA site was evalu- ated. Furthermore, differences in plaque composition and type between both the Max NC and MLA site were compared. When normally distributed, continuous variables were expressed as mean (± standard deviation) and compared with independent sample t-test for unpaired samples or the dependent t-test for paired samples. If not normally distrib- uted, variables were presented as median and interquartile range. Unpaired samples were analyzed using non-parametric Mann-Whitney test and paired variables were analyzed with Wilcoxon signed rank tests. Categorical variables were expressed as numbers and percentages, and compared with the Chi-square test. A p-value of p<0.05 was considered signifi cant.

RESULTS

Overall, 77 patients were evaluated. Patient characteristics are presented in Table 1. In total, 169 vessels were analyzed with VH IVUS, in 30 vessels (18%) previous PCI was per- formed and these vessels were therefore excluded. Thus, 139 vessels were included for further analysis.

The spatial relationship between the Max NC and MLA site is demonstrated in Figure 1.

Interestingly, the Max NC site was located in the same location as the MLA site in only

7 vessels (5%). In the remaining vessels, the Max NC site was located proximally to the

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Table 1. Patient characteristics of study population.

n (%)

Age (years) 59 ± 10

Gender (% male) 64 (70%)

Risk factors for CAD

Obesity (Body mass index ≥ 30 kg/m

) 21 (23%)

Diabetes 27 (29%)

Hypertension† 54 (59%)

Hypercholesterolemia‡ 47 (51%)

Family history of CAD 44 (48%)

Smoking 32 (35%)

Aspirin use 49 (53%)

Statin use 60 (65%)

Previous PCI 25 (27%)

Previous myocardial infarction 17 (19%)

Presentation with ACS 62 (67%)

Data are absolute values, percentages or means ± standard deviation.

†Defi ned as systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or the use of antihypertensive medication.

‡Serum total cholesterol ≥230 mg/dL or serum triglycerides ≥200 mg/dL or treatment with lipid lowering drugs.

Abbreviations: CAD, coronary artery disease; ACS, acute coronary syndrome, PCI, percutaneous coronary intervention.

Figure 1. Spatial relationship of the maximum necrotic core site (Max NC) as compared to minimal

lumen area (MLA). In the majority of vessels the site of Max NC is located proximal to site of MLA.

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MLA site in 92 vessels (66%) and located distally from the MLA site in 40 vessels (29%).

Accordingly, the mean difference (mm) between the MLA site and Max NC site was 10.8

± 20.6 mm (P<0.001). Regarding the more proximally located Max NC sites, the mean difference between Max NC and MLA site was 19.6 ± 19.7 mm (P<0.001). Concerning the more distally located Max NC sites, the mean difference between Max NC site and MLA was 7.4 ± 7.8 mm (P<0.001). The differences in distance between Max NC site and MLA site were assessed between patients with ACS (n=52) and patients with stable CAD (n=25). Interestingly, no difference in distance between Max NC and MLA was observed (10.7 ± 20.5 mm for stable CAD vs. 10.9 ± 20.8 mm for patients with ACS, P=0.699). Figure 2 shows an example of a vessel with the site of greatest vulnerability located proximal to the MLA site.

The differences in absolute and relative plaque composition between the Max NC and MLA site are demonstrated in Table 2. As expected, the Max NC site contained signifi cantly more necrotic core as compared to the MLA site (31% (23 - 40%) versus 19% (10 - 19%), P<0.001). Moreover, the MLA site contained signifi cantly more fi brotic tissue than the Max NC site (57% (47 - 65%) versus 49% (41 - 57 %), P<0.001). Furthermore, the MLA site contained signifi cantly more fi bro-fatty tissue than the Max NC site (13% (6 - 24%) versus 6% (3 - 12%), P<0.001). Lastly, plaque burden was signifi cantly larger at the MLA site than at Max NC site (63% (54 - 74%) versus 59% (43 - 68%), P<0.001).

Figure 2. Example of a coronary artery with the site of maximum necrotic core (Max NC) located

proximal from the minimal lumen area (MLA) site. Panel A demonstrates a longitudinal view of

the intravascular ultrasound (IVUS) images. As demonstrated, the Max NC site (C) is not located at

the minimum lumen area (MLA) site (B), but 16.4 mm proximal of the MLA site. Panel B shows the

grayscale cross-sectional slices and the corresponding virtual histology IVUS images of the MLA

site. Panel C shows the grayscale cross-sectional slices and the corresponding virtual histology IVUS

images for the Max NC site. Interestingly, although the MLA site has signifi cant luminal narrowing

(lumen area of 2.1 mm2) the Max NC site demonstrated a thin cap fi broatheroma (TCFA).

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The difference in plaque type between MLA and Max NC sites was assessed. Interest- ingly, pathological intimal thickening was most often observed at the MLA site as com- pared to the Max NC site (26% versus 1%, P<0.001). In addition, lesions at the Max NC site were more often classifi ed as a fi broatheroma than lesions at the MLA site (71% versus 60%, P=0.04). Furthermore, the percentage of fi brocalcifi c plaque was similar at both the MLA site and Max NC site (5% versus 4%, P=0.78). Importantly, as demonstrated in Figure 3, a signifi cantly higher percentage of TCFA was present at Max NC site as compared to the MLA site (24% versus 9%, P<0.001). Moreover, if TCFA was identifi ed at the Max NC site, only in 33% of cases the MLA site also demonstrated a TCFA. No signifi cant differ- ences were observed between plaque type and composition between proximal and distal Max NC sites (Table 3).

Table 2. Comparison of plaque composition between maximum necrotic core (Max NC) site and minimum lumen area site (MLA).

VH IVUS

plaque composition

Max NC site MLA site P-value

Lumen area (mm

) 7.3 (5.1 - 10.9) 4.3 (3.1 - 6.9) <0.001 Vessel area (mm

) 18.7 (14.9 – 23.8) 14.0(10.4 - 17.4) <0.001 Plaque area (mm

) 11.2 (8.5 - 13.6) 8.9 (6.1 - 11.2) <0.001 Plaque burden 59% (49 – 68%) 63% (54 – 74%) <0.001 Fibrotic (mm

) 3.8 (2.6 - 4.9) 3.2 (2.1 - 4.6) 0.01 Fibro-fatty (mm

) 0.5 (0.2 - 1.0) 0.7 (0.2 - 1.5) <0.001 Necrotic core (mm

) 2.3 (1.5 - 3.1) 1.2 (0.5 - 1.8) <0.001 Dense calcium (mm

) 0.8 (0.3 - 1.3) 0.3 (0.1 - 0.8) <0.001

Fibrotic 49% (41 – 57%) 57% (47 – 65%) <0.001

Fibro-fatty 6% (3 – 12%) 13% (6 – 24%) <0.001

Necrotic core 31% (24 – 40%) 19% (9 – 28%) <0.001 Dense calcium 10% (5 – 16%) 6% (1 – 12%) <0.001 Data are presented as medians and interquartile range

Figure 3. Difference in presence of thin cap fi broatheroma (TCFA) between minimum lumen area (MLA) site and maximum necrotic core (Max NC) site.

As demonstrated, TCFA was signifi cantly

more often observed at the Max NC site as

compared to the MLA site.

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DISCUSSION

The present study evaluated the spatial relationship between the site of most severe nar- rowing and greatest vulnerability with the use of invasive VH IVUS. Interestingly, it was demonstrated that the site of greatest vulnerability (defi ned as maximum necrotic core area) was rarely located at the site of most severe narrowing (defi ned as the minimum lumen area). Most often (in 66% of vessels), the site of greatest vulnerability was located proximal from the site of most severe narrowing. Of particular interest was the fi nding that a higher percentage of TCFA (plaque phenotype with high-risk of rupture) was dem- onstrated at the site of greatest vulnerability.

Histopathological studies have observed that high-risk plaque features include the presence of a large necrotic core, infl ammatory cells at the shoulders of the plaque and a thin fi brous cap.

Indeed, the rupture of a thin cap fi broatheroma is thought to be the primary cause of an acute coronary syndrome.

Moreover, several landmark angio- graphic studies have reported that the presence of plaque rupture was poorly related to angiographic degree of luminal narrowing.

As demonstrated during the follow up of patients admitted for acute myocardial infarction, almost two thirds of plaques prone to rupture were located in non fl ow-limiting atherosclerotic lesions, and only a minority were located in severely obstructed lesions.

Interestingly, the fi ndings of the current study support this concept, demonstrating invasively with VH IVUS that the more vulnerable sites were not at the site of most severe narrowing, but were located more proximally.

Therefore, it could be of importance to identify the presence of a high-risk lesion with either non-invasive or invasive modalities, even at sites without the presence of signifi cant luminal narrowing.

Table 3. Comparison of plaque composition and type between the maximum necrotic core (Max NC) site located proximal and distal from the minimum lumen area (MLA).

VH IVUS characteristics

Max NC site proximal to MLA site

Max NC site distal from MLA site

P-value

Plaque composition

Fibrotic 49% (41 - 56%) 49% (39 - 58%) 0.96

Fibro-fatty 6% (3 – 12%) 5% (3 - 10%) 0.40

Necrotic core 31% (24 - 40%) 34% (24 - 39%) 0.74

Dense calcium 10% (6 – 14%) 10% (4 - 19%) 0.91

Plaque type

Pathological intimal thickening 0 (0%) 1 (1%) 0.51

Fibroatheroma 32 (24%) 63 (48%) 0.18

Thin cap fi broatheroma 7 (5%) 23 (17%) 0.35

Fibrocalcifi c plaque 1 (1%) 5 (4%) 0.46

Data are presented as numbers, percentages, medians and interquartile range

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Previous reports exploring the relation between the location of the site of most severe narrowing and site of greatest vulnerability using VH IVUS have demonstrated compa- rable fi ndings.

Rodriguez et al. performed VH IVUS in 40 patients and assessed the difference in plaque characteristics between plaque rupture site and site of most severe narrowing.

Similar to the current fi ndings, the authors demonstrated a signifi cantly higher percentage of necrotic core at the plaque rupture site (16.8%) as compared with the site of most severe narrowing (11.8%). Consequently, the authors concluded that the plaque rupture sites had a worse plaque phenotype than the site of most severe narrowing. In addition, Konig et al. performed an analysis with VH IVUS in 48 patients and demonstrated that the site of severest stenosis was not always located at the site with the highest percentage necrotic core.

However, the aforementioned investigations performed an analysis on a per-lesion basis, whereas the present study investigated the entire vessel with VH IVUS. Indeed, a vessel-based analysis provides a more complete evaluation and relevant vulnerable plaque sites are less likely to be missed.

A possible explanation for the current fi ndings could be the relation between presence of positive remodeling and plaque vulnerability. Indeed, compensatory enlargement of the vessel wall, including eccentric plaque growth, is strongly associated with necrotic core area, macrophage infi ltration and the occurrence of acute cardiac events.

Also during in vivo VH IVUS studies, a similar connection between positive remodeling and plaque composition has been reported.

However, with traditional invasive coronary angiography, lesions with outward (positive) remodeling are frequently missed. Invasive coronary angiography is only able to show the contrast fi lled lumen and is unable to visualize atherosclerosis in the arterial wall (with the exception of large calcifi cations) and reference segments.

As a consequence, coronary angiography alone will not detect the exact location of the site of greatest vulnerability in the majority of patients. Furthermore, due to the difference in location between the site of most severe narrowing and the site of greatest vulnerability, percutaneous coronary intervention (PCI) of the high risk lesion will be less accurate. Incomplete coverage of a high-risk lesion can lead to increased rates of in-stent restenosis, dissection and stent thrombosis.

Therefore, identifi cation of the site of greatest vulnerability, in addition to the site of most severe narrowing, could possi- bly be of importance for clinical management and outcome. In addition, PCI is most often performed in fl ow-limiting lesions in order to relieve chest pain symptoms. However, no consensus exists regarding the type of treatment for vulnerable regions and systemic anti-atherosclerotic measures (statins) are currently preferred. Nevertheless, studies are ongoing evaluating other alternatives (e.g. bio-absorbable stents) for effective treatment of vulnerable plaque regions.

The following limitations of the present study should be considered. First, the present study only evaluated 77 patients in a single center. Ideally, a larger patient population should be studied, preferably in a multicenter setting. Secondly, due to acoustic shadow- ing it is diffi cult to assess plaque composition behind severe calcifi cations on VH IVUS.

Therefore, possibly small non-calcifi ed elements within the more heavily calcifi ed parts

of the plaque may have been missed. Lastly, detection of the thin fi brous cap (<65 μm)

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is not yet feasible as VH IVUS has limited radial resolution of only 100 μm. A technique such as optical coherence tomography (OCT) imaging would permit these measurements;

however, OCT was not performed in the present study.

Conclusion

The present fi ndings demonstrate that the site of greatest vulnerability is rarely at the

site of most severe narrowing. Moreover, the site of greatest vulnerability is frequently

located proximal from the site of most severe narrowing. Potentially, due to insuffi cient

identifi cation of the high risk lesion, a vulnerable site might remain concealed.

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